Stable liquid desoximethasone compositions with reduced oxidized impurity

ABSTRACT

The present invention relates to a stable liquid formulation comprising desoximetasone, isopropyl myristate, a C 2 -C 4  alcohol and a stabilizing agent. Specifically, the present invention provides a liquid formulation comprising: a) about 0.01 wt % to about 2.5 wt % desoximetasone; b) about 10 wt % to about 70 wt % isopropyl myristate; c) about 20 wt % to about 70 wt % C 2 -C 4  alcohol; and d) a stabilizing agent selected from the group consisting of an oleaginous vehicle and a propellant, wherein the stabilizing agent is in an amount sufficient to reduce the formation of less than about 1 wt % 17-carboxy-9α-fluoro-11β-hydroxy-16a-methyl-androsta-1,4-diene-3-one under an accelerated storage condition.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) of the U.S.Provisional Application No. 60/685,676 filed May 27, 2005, thedisclosure of which is incorporated by reference in its entirety herein.

FIELD OF THE INVENTION

The present invention relates to a stable liquid formulation comprisingdesoximetasone, isopropyl myristate, a C₂-C₄ alcohol and a stabilizingagent. The present liquid formulation is characterized by enhancedstability and reduced oxidized impurity(17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one).The present invention also relates to a process for preparing a stableliquid formulation and a method of treating skin conditions includingpsoriasis.

BACKGROUND OF THE INVENTION

Chronic inflammatory disease such as psoriasis is a prevalent skindisease characterized by circumscribed red patches covered with whitescales. The symptoms ranges from minimal lesions of the elbows and kneesto a large number of lesions scattered over the skin. Current therapy ofpsoriasis includes topical administration of corticosteroid with thedosage forms of cream, ointment, and lotion.

U.S. Pat. No. 5,990,100 (the '100 patent) discloses isopropyl myristateas an active agent for treating psoriasis. The '100 patent furtherdiscloses the combined use of isopropyl myristate and an anti-psoriaticagent to form a more effective composition in treating psoriasis thaneither agent alone. Specifically, example 1 of the '100 patent disclosesa formulation containing 40 wt % isopropyl myristate, 0.1 wt % sodiumlauryl sulfate, 1.5 wt % polysorbate 80, 3.4 wt % water and 55 wt %ethanol. According to the '100 patent, topical application of theaerosolized formulation containing isopropyl myristate followed bytopical application of calcipotriol ointment, desonide ointment orfluocinolone acetonide powder are more effective in treating psoriasisthan either agent by itself.

U.S. Pat. No. 5,776,433 (the '433 patent) discloses an aerosolizedflunisolide formulation useful in the treatment of inflammation of thenasal mucosa. In the '433 patent, hydrofluorocarbons is used as thepropellant in a metered dose aerosol system containing amicrocrystalline suspension of a steroid (i.e., flunisolidehemihydrate), propylene glycol, polyethylene glycol 3350, citric acid,sodium citrate, butylated hydroxyanisole, edetate disodium, benzalkoniumchloride, and purified water. The '433 patent discloses that ethanolfunctions to solubilize the flunisolide, and the presence of waterenhances to stabilize flunisolide. The '433 patent suggests the use ofpropellant to propel a plurality of flunisolide doses. While the '433patent suggests the use of glass aerosol vial or aluminum aerosol vialhaving an interior chamber coated with an inert resin, it remains silentas to the agent(s) that may affect flunisolide stability.

U.S. Pat. Nos. 6,610,273 (the '273 patent) and 6,315,985 (the '985patent) disclose that 20-ketosteroids rapidly begin to degrade when comein direct contact with aluminum oxide (Al₂O₃). 20-ketosteroids reaches ahigh degree of degradation (100% degradation) after addition of Al₂O₃ toan aerosolized formulation containing 20-ketosteroids. The '273 patentand '985 patent suggest the use of epoxy-phenolic lacquer or glass as aninert surface to minimize the degradation. Notably, the '985 patentstates “the use of certain antioxidants such as ascorbic acid andascorbyl palmitate (but not vitamin E) appeared to enhance chemicalstability, while the use of oleic acid appeared to reduce chemicalstability.” (See, the '985 patent, col. 12, lines 2-5). Thus, the '985patent suggests that the 20-ketosteroid degradation in the presenceAl₂O₃ is inhibitable by anti-oxidants.

We surprisingly discovered that a liquid formulation comprisingisopropyl myristate and desoximetasone suffers from oxidation ofdesoximetasone. The liquid formulation, even when stored with an inertsurface (e.g., glass or canister) begins to deteriorate (i.e., formationof an oxidized impurity) when subjected to accelerated storageconditions (e.g., 40° C., 75% relative humidity for 3 months),indicating unsuitability of the product. Although present in smallamounts, the level of oxidized impurity (after long-term storage)exceeds the qualification threshold and identification thresholdcalculated based on the maximum daily dosage. (See, ICH Guidance forIndustry Q3B® Impurities in New Drug Products, November, 2003).

There is a continuing need for developing an aerosolized formulation ofdesoximetasone and isopropyl myristate that contains minimum acceptablelevels of oxidized impurity. Prior art endeavors in this field havefallen short because no stable aerosolized formulations comprisingdesoximetasone and isopropyl myristate have been identified. The presentinvention meets this need by providing the use of a stabilizing agent inan aerosolized formulation suitable for long-term storage.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a stable liquidformulation of desoximetasone and isopropyl myristate that contains lessthan about 1 wt % oxidized impurity.

In one aspect, the present invention provides a liquid formulationcomprising:

-   -   a) about 0.01 wt % to about 2.5 wt % desoximetasone;    -   b) about 10 wt % to about 70 wt % isopropyl myristate;    -   c) about 20 wt % to about 70 wt % C₂-C₄ alcohol; and    -   d) a stabilizing agent selected from the group consisting of an        oleaginous vehicle and a propellant,    -   wherein the stabilizing agent is present in a sufficient amount        to reduce the formation of less than about 1 wt %        17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one        after storage at 40° C., 75% relative humidity for 3 months.

Preferably, the C₂-C₄ alcohol is either linear or branch. Preferably,the C₂-C₄ alcohol is ethyl alcohol. Preferably, the C₂-C₄ alcohol isisopropanol.

Preferably, oleaginous vehicle is selected from the group consisting ofmineral oil, and light mineral oil. More preferably, the oleaginousvehicle is mineral oil.

Optionally, the stabilizing vehicle is a mixture of an oleaginousvehicle and a skin conditioning agent.

Preferably, the skin conditioning agent is an ester of glycerin andC₁₅-C₂₅ fatty acid. Preferably, the ester is a monoester. Morepreferably, the C₁₅-C₂₅ fatty acid is oleic acid. More preferably, theskin conditioning agent is glyceryl oleate.

Preferably, the skin conditioning agent is a C₁₅-C₂₅ fatty alcohol. Morepreferably, the C₁₅-C₂₅ fatty alcohol selected from the group consistingof lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol,linoleyl alcohol, and oleyl alcohol. More preferably, the C₁₅-C₂₅ fattyalcohol is oleyl alcohol.

Preferably, the propellant is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, butane,isobutane, propane, and dimethyl ether.

Preferably, the stable aerosolized formulation of desoximetasone andisopropyl myristate further comprises a surfactant.

Preferably, the surfactant selected from the group consisting of sodiumlauryl sulfate, and polysorbate 80.

Preferably, the surfactant is present in the amount of about 0.5 wt % toabout 5 wt %.

Preferably, the stable aerosolized formulation of desoximetasone andisopropyl myristate further comprises water.

Preferably, the water is present in the amount of about 1 wt % to about10 wt %.

Preferably, the accelerated storage condition is 40° C., 75% relativehumidity for a time period of 3 months. More preferably, the acceleratedstorage condition is 50° C. for a time period of 1 month.

Preferably, the stable aerosolized formulation of desoximetasone andisopropyl myristate is delivered via a pump delivery system. Morepreferably, the liquid formulation is delivered via an aerosolizeddelivery system.

Preferably, the aerosolized delivery system contains a can equipped witha continuous valve.

Preferably, the present liquid formulation may be in a foam dosage form.

Preferably, the present liquid formulation may be in a lotion dosageform.

In another aspect, the present invention provides a method of treating acorticosteroid responsive dermatosis comprising the step of topicaladministering the stable liquid formulation of desoximetasone andisopropyl myristate.

Preferably, the corticosteroid responsive dermatosis is selected fromthe group consisting of plaque psoriasis, and atopic dermatitis.

In another aspect, the present invention provides a process forpreparing a stable liquid formulation of desoximetasone and isopropylmyristate comprising:

-   -   a) mixing desoximetasone in ethyl alcohol to from a mixture;    -   b) adding isopropyl myristate in the mixture; and    -   c) adding stabilizing agent to the mixture in an amount        sufficient to reduce the formation of less than about 1 wt %        oxidized impurity        (17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one)        under an accelerated storage condition.

In yet another aspect, the present invention provides a process forpreparing a stable aerosolized formulation of desoximetasone andisopropyl myristate comprising the step of filling an aerosolformulation into a container equipped with a continuous valve, saidaerosol formulation contains:

-   -   a) about 0.01 wt % to about 2.5 wt % desoximetasone;    -   b) about 10 wt % to about 70 wt % isopropyl myristate;    -   c) about 20 wt % to about 70 wt % C₂-C₄ alcohol; and    -   d) a stabilizing agent selected from the group consisting of a        mixture of mineral oil and glyceryl oleate, a mixture of mineral        oil and oleyl alcohol, and a propellant in an amount sufficient        to reduce the formation of less than about 1 wt % oxidized        impurity        17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one        under an accelerated storage condition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 1 at time zero.

FIG. 2 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 1 after storage at 40° C./75% relativehumidity for 12 weeks.

FIG. 3 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 5 (containing anti-oxidant of citric acidand tartaric acid) at time zero.

FIG. 4 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 5 (containing anti-oxidant of citric acidand tartaric acid) after storage at 50° C. for 4 weeks.

FIG. 5 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 7 (containing a stabilizing agent of amixture of mineral oil and oleyl alcohol) at time zero.

FIG. 6 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 7 (containing a stabilizing agent of amixture of mineral oil and oleyl alcohol) after storage at 40° C./75%relative humidity for 12 weeks.

FIG. 7 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 11 (containing a stabilizing agent of amixture of mineral oil and glyceryl oleate) at time zero.

FIG. 8 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 11 (containing a stabilizing agent of amixture of mineral oil and glyceryl oleate) after storage at 40° C./175%relative humidity for 12 weeks.

FIG. 9 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 12 (containing a stabilizing agent of apropellant) at time zero.

FIG. 10 depicts the entire HPLC chromatogram summarizing the impurityprofile for formulation no. 11 (containing a stabilizing agent of apropellant) after storage at 40° C./75% relative humidity for 12 weeks.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the definition of terms are listed as follow:

“stabilizing agent” refers to an agent that improves stability of theliquid formulation and prevent the formation of oxidized impurity(17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one);

“oleaginous vehicle” refers to a solvent that resembles or having theproperties of oil such as vegetable oil (corn, cottonseed, olive, peanutand sesame seed oils) or mineral oil;

“propellant” refers to a compound effective in dispensing the activeingredients into a fine mist or foam;

“mineral oil” refers to a mixture of refined liquid saturatedhydrocarbons obtained from petroleum. Viscosity (at 40° C.) and specificgravity of mineral oil usually is >34.5 cSt and between 0.845-0.905,respectively. CAS registry no. is 8012-95-1;

“light mineral oil” refers to a mixture of refined liquid saturatedhydrocarbons obtained from petroleum. It is less viscous and has lowerspecific gravity than mineral oil. Viscosity (at 40° C.) and specificgravity of light mineral oil usually is <33.5 cSt and between0.818-0.880, respectively;

“glycerin” refers to a polyhydric alcohol that conforms generally to theformula: HOCH₂CH(OH)CH₂OH;

“oleyl alcohol” refers to the unsaturated fatty alcohol that conformsgenerally to the formula: CH₃(CH₂)₇CH═CH(CH₂)₈OH;

“skin conditioning agent”—for purposes of the present invention, “skinconditioning agent” encompasses a monoester of a glycerin and a C₁₅-C₂₅fatty acid and a C₁₅-C₂₅ fatty alcohol;

“fatty alcohol” refers aliphatic alcohol that occurs naturally in freeform (component of the cuticular lipids) but more usually in esterified(wax esters) or etherified form (glyceryl ethers);

“ester” refers to any one of a group of organic compounds with generalformula RCO₂R′ (where R and R′ are alkyl groups or aryl groups) that areformed by the reaction between an alcohol and an acid;

“monoester” refers to an ester having only one ester group;

“oxidized impurity”—for purposes of the present invention, “oxidizedimpurity” identified in the present formulation having a relativeretention time of 1.26, a retention time usually between 20 and 30minutes, and physical chemical properties as detailed in the “Examplesection” refers to17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one;

“aerosol” refers to the products which depends upon the power of aliquefied or compressed gas to disperse the active ingredients in afinely dispersed mist, foam or semisolid. For purpose of the presentinvention, pump systems which also dispense the active ingredients inthe form of a finely dispersed mist (although of greater particle size)are intended to be encompassed as aerosol;

“accelerated storage condition” refers to storage of a liquidformulation under the conditions of either 40° C., 75% relative humidityfor 12 weeks or 50° C. for 4 weeks. These storage conditions areequivalent to that of 25°-30° C., 60% relative humidity for twenty-four(24) months (i.e., long-term storage).

“topical administration” refers to local administration to the skin ofthe liquid or semi-solid formulation and its various embodiments;

“mammal” refers to a class of higher vertebrates comprising man and allother animals that nourish their young with milk secreted by mammaryglands and have the skin usually more or less covered with hair; and

“treating” is intended to encompass relieving, alleviating oreliminating at least one symptom of a dry skin diseases in a mammal.

Unless otherwise specified, % refers to % wt; and % wt refers to % ofweight of respective component with respect to the total weight of thecomposition.

Inventors of the present invention unexpectedly discovered a stableliquid formulation comprising desoximetasone, isopropyl myristate, C₂-C₄alcohol and a stabilizing agent and a method for treating a patient fora skin condition, comprising the step of administering such a stableliquid formulation. The present formulation and method offer significantadvantages over the prior art in that it provides enhanced stability ofthe liquid formulation that is useful in treating the skin conditions.

While the use of epoxy-phenolic lacquer or glass as an inert surface issuggested to reduce the degradation of 20-ketosteroids ($ee, U.S. Pat.No. 6,610,273), inventors of the present invention found that there isstill a significant formation of oxidized impurity in a liquidformulation comprising desoximetasone, isopropyl myristate and C₂-C₄alcohol. Inventors of the present invention characterized and identifiedthe oxidized impurity as17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one.The formation of the oxidized impurity occurs upon accelerated storageconditions, even when the liquid formulation is stored (i.e., in directcontact with) in glass.

In its active pharmaceutical ingredient (API) form, desoximetasone hasthree (3) impurities; namely: i) impurity S, ii) 17-desoxiosido- andiii)17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one. Ofthese 3 impurities, only the17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one wasfound to increase in the liquid formulation upon accelerated storageconditions. This finding indicates that this particular impurity of17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-oneuniquely increases upon accelerated storage conditions with respect to aliquid formulation comprising desoximetasone, isopropyl myristate, C₂-C₄alcohol.

Because the level of the oxidized impurity exceeds the qualificationthreshold and identification threshold calculated based on the maximumdaily dosage, it renders the liquid formulation unsuitable forcommercial use.

Inventors of the present invention unexpectedly discovered that theformation of17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one isdifferent from degradation of 20-ketosteroids via its interaction ofAl₂O₃. While the interaction of Al₂O₃ is completely blocked byanti-oxidants (See, U.S. Pat. No. 6,315,985), the formation of17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one isnot affected by addition of anti-oxidants at all (See, Table 5 of“Example” Section below). On the contrary, additional impurities werefound to be generated (See, Table 6 of “Example” Section below).

Inventors of the present invention surprisingly discovered that additionof a stabilizing agent enhances the stability of the liquid formulationcomprising desoximetasone, isopropyl myristate and a C₂-C₄ alcohol.Without wishing to be bound by a theory, it is believed that thestabilizing agent inhibits the formation of the oxidized impurity(17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one),probably via an oxidation pathway that is not sensitive toanti-oxidants. According to the present invention, the addition of astabilizing agent therefore offers a much improved liquid formulationcomprising desoximetasone, isopropyl myristate and a C₂-C₄ alcohol.

Accordingly, the present invention is directed to a stable liquidformulation containing a steroid (i.e., desoximetasone) in therapeuticamounts to alleviate the symptoms of dermatosis skin conditions. For thepurposes of the present invention, desoximetasone encompasses the saltforms of desoximetasone as exemplified by desoximetasone hydrochlorideor desoximetasone acetate.

The therapeutically amount of the desoximetasone in the present stableliquid formulation is generally within the range of from about 0.01 wt %to 2.5 wt % of the formulation. Preferably, the desoximetasone ispresent in the amount of about between about 0.1 wt % to about 1 wt %.More preferably, the desoximetasone is present in the amount of about0.25 wt %.

Accordingly, the present invention provides a stable liquid formulationcontaining isopropyl myristate. Preferably, isopropyl myristate ispresent in the amount of about from about 10 wt % to about 70 wt %. Morepreferably, isopropyl myristate is present in the amount of about 25 wt% and 55 wt %. More preferably, isopropyl myristate is present in theamount of about 40 wt %.

Accordingly, the present invention also provides a stable liquidformulation containing a C₂-C₄ alcohol. The C₂-C₄ alcohol may encompassa linear or branch C₂-C₄ alcohol. Preferably, the C₂-C₄ alcohol is ethylalcohol. Preferably, the C₂-C₄ alcohol is isopropanol.

Preferably, the C₂-C₄ alcohol is present in the amount of from about 20wt % to about 70 wt %. More preferably, the C₂-C₄ alcohol is present inthe amount of from about 30 wt % to about 60 wt %. More preferably, theC₂-C₄ alcohol is present in the amount of about 40 wt %.

In one preferred embodiment, stabilizing agent used in the presentinvention is an oleaginous vehicle.

Preferably, oleaginous vehicle includes, but not limited to, mineraloil, and light mineral oil. Other suitable oleaginous vehicle includesapricot kernel oil, canola oil, castor oil, coconut oil, corn oil,cottonseed oil, olive oil, soybean oil or vegetable oil.

Preferably, oleaginous vehicle is present in the amount of about 10 wt %to about 60 wt %. More preferably, oleaginous vehicle is present in theamount of about 20 wt % and 50 wt %. More preferably, oleaginous vehicleis present in the amount of about 40 wt %.

Optionally, the stabilizing agent is a mixture of an oleaginous vehicleand a skin conditioning agent. Such a mixture of an oleaginous vehicleand a skin conditioning agent would also found to be effective toprevent the formation of oxidized impurity when added into the liquidformulation.

In another preferred embodiment, skin conditioning agent is a ester of aglycerin and a C₁₅-C₂₅ fatty acid. Preferably, the ester is a monoester.Preferably, the C₁₅-C₂₅ fatty acid is oleic acid. Preferably, the esteris glyceryl oleate.

In another preferred embodiment, skin conditioning agent is a C₁₅-C₂₅fatty alcohol. An unsaturated C₁₅-C₂₅ fatty alcohol includes, but notlimited to, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearylalcohol, linoleyl alcohol, oleyl alcohol and the like. More preferably,the C₁₅-C₂₅ fatty alcohol is oleyl alcohol.

Preferably, skin conditioning agent is present in the amount of about0.5 wt % to about 10 wt %. More preferably, skin conditioning agent ispresent in the amount of about 1 wt % and about 8 wt %. More preferably,skin conditioning agent is present in the amount of about 5 wt %.

Preferably, stabilizing agent used in the present invention is a mixtureof mineral oil and oleyl alcohol.

Preferably, stabilizing agent used in the present invention is a mixtureof mineral oil and glyceryl oleate.

Preferably, the mixture of an oleaginous vehicle and a skin conditioningagent is present in an amount sufficient to inhibit the formation ofoxidized impurity after accelerated storage condition (e.g., 40° C./75%relative humidity for 12 weeks or 50° C. for 4 weeks).

In another preferred embodiment, stabilizing agent used in the presentinvention is propellant. Preferred propellant in the present stableformulation includes, but not limited to, 1,1,1,2-tetrafluoroethane, and1,1,1,2,3,3,3-heptafluoropropane. Suitable propellant also includesbutane, isobutane, propane, and dimethyl ether. More preferably, thepropellant is 1,1,1,2-tetrafluoroethane.

Preferably, propellant is present in an amount sufficient to inhibit theformation of oxidized impurity after accelerated storage condition(e.g., 40° C./75% relative humidity for 12 weeks). Preferably,propellant is present in about 20 wt % to about 95 wt %. Morepreferably, propellant is present in about 40 wt % to about 80 wt %.More preferably, propellant is present in about 75 wt %.

The stable liquid formulation may further comprise surfactant.Preferably, the surfactant includes, but not limited to sodium laurylsulfate, and polysorbate 80.

Preferably, surfactant is present in the amount of about 0.5 wt % toabout 5 wt %. More preferably, surfactant is present in the amount ofabout 1 wt % and about 3 wt %. More preferably, surfactant is in theamount of about 1 wt %.

The stable liquid formulation may further comprise water. Preferably,water is present in the amount of about 1 wt % to about 10 wt %. Morepreferably, water is present in the amount of about 2 wt % and 6 wt %.More preferably, water is present in the amount of about 3 wt %.

Preferably, the accelerated storage condition is 40° C., 75% relativehumidity for a time period of 3 months. Preferably, the acceleratedstorage condition is 50° C. for a time period of 1 month.

The present liquid formulation may be delivered via suitable deliverysystem. Preferably, the present liquid formulation is delivered via anaerosolized delivery system. Preferably, the present liquid formulationmay be delivered via a pump delivery system. Preferably, the aerosolizeddelivery system contains a can equipped with a continuous valve.Preferably, the aerosolized delivery system contains a can equipped witha meter-dosed valve.

In another preferred embodiment, the present invention provides a foampharmaceutical composition containing a corticosteroid (e.g.,desoximetasone), isopropyl myristate, C₂-C₄ alcohol, an oleaginousvehicle as a stabilizing agent, and a foam-forming agent. Preparation ofa foam pharmaceutical composition is known. Suitable foam-forming agentsinclude, but not limited to, surfactants exemplified by cetyl alcohol,stearyl alcohol, ethoxylated stearyl alcohol, polawax, and the like.(See, e.g., Sanders P. “Aqueous Alcohol Aerosoal Foams”; D&CI/August1966). One or more foam-forming agent(s) may be used. Properconcentration of foam-forming agents may easily be optimized by oneskill in the art.

The present liquid formulation may also be formulated into a quick-breakfoam. When applied to skin, the foam composition is initially in theform of a mousse-like foam, but will slowly break down at the skintemperature to liquid. This would allow the desoximetasone and isopropylmyristate to saturate the treatment site. Quick-break foaming agentsthat can be used in the present invention are generally known (ee e.g.,WO 85/01876). It is preferred that the quick-breaking foaming agentcomprises an aliphatic alcohol, water, a fatty alcohol and asurface-active agent.

In yet another preferred embodiment, the present invention provides alotion pharmaceutical composition containing a corticosteroid (i.e.,desoximetasone), isopropyl myristate, C₂-C₄ alcohol, a stabilizing agent(e.g., an oleaginous vehicle) in an isopropyl myristate base. Lotionsmay be liquid preparations. The present liquid formulation may be anemulsified or non-emulsified lotion. Preferably, the present liquidformulation is a non-emulsifying lotion. Optionally, the lotions maycontain an antimicrobial preservative and other appropriate excipientssuch as a thickening agent (to increase viscosity).

The present invention provides a method of treating a corticosteroidresponsive dermatosis comprising the step of topical administering theaerosolized formulation. The corticosteroid responsive dermatosis isselected from the group consisting of plaque psoriasis, and atopicdermatitis.

The present invention provides a method of preparing a stable liquidformulation. The preparation method is detailed hereinafter.

Method of Preparation

In one preferred embodiment, the present invention provides a method forpreparing a stable liquid formulation, comprising the steps of:

-   -   a) combining desoximetasone, C₂-C₄ alcohol and isopropyl        myristate to form a mixture;    -   b) optionally adding water, sodium lauryl sulfate, or        polysorbate 80 into the mixture; and    -   c) adding a stabilizing agent into the mixture to form a stable        liquid formulation.

Preferably, the stabilizing agent is selected from the group consistingof an oleaginous vehicle and a propellant. Preferably, the oleaginousvehicle is mineral oil or light mineral oil. Preferably, the stabilizingagent is a mixture of mineral oil and glyceryl oleate. Preferably, thestabilizing agent is a mixture of mineral oil and oleyl alcohol.Preferably, the stabilizing agent is a propellant. Preferably, thestabilizing agent is in an amount sufficient to reduce the formation ofless than about 1 wt % oxidized impurity under an accelerated storagecondition.

The present invention is directed to a method of treating skinconditions in a mammal. More particularly, the present inventionprovides a method of treating skin conditions in a patient by providingan improved stable liquid formulation comprising therapeutic effectiveamounts of desoximetasone and isopropyl myristate. According to thepresent invention, the term “patient” will encompass any mammalrequiring treatment for skin conditions, particularly a human patientsuffering from dermatosis.

For the purpose of the present invention, dermatosis condition includes,but are not limited to, all conditions of psoriasis and atopicdermatitis.

The dosage for the desoximetasone and isopropyl myristate of theinvention will vary depending on several factors, including, but notlimited to, the age, weight, and species of the patient, the generalhealth of the patient, the severity of the symptoms in dermatosis skinconditions.

Analytical Protocol:

Contents of desoximetasone and its related impurities (including theoxidized impurity) were determined by using the following HighPerformance Liquid Chromatography (HPLC) protocol. In this protocol, aHPLC instrument with a chromatograph and an ultra-violet detector wasused. The HPLC condition was:

Column Waters Symmetry C18, 4.6 × 250 mm, 5 μm particle diameter FlowRate 0.8 ml/min isocratic Detection UV at 275 nm Injection Volume 5 μLColumn Temperature 25° C. Mobile Phase 360 grams of acetonitrile wasdissolved in 600 grams of water to it 30 grams of methanol was addedfollowed by 10 grams of acetic acid and mixed.

Having now generally described this invention, the same will be betterunderstood by reference to the following Examples, which are providedherein solely for purposes of illustration only and are not intended tobe limiting of the invention or any embodiment thereof, unless sospecified. All parts and percentages referred to in this specificationand the appended claims are by weight unless otherwise specified.

EXAMPLES Example 1 Impurities Present in Desoximetasone API

We analyzed the impurities present in the active pharmaceuticalingredient (API) dexosimetasone using HPLC technique. A total of notmore than 1.0% impurities were found to be present in the dexosimetasoneAPI. Of the total impurities found, three (3) main impurities wereidentified to be:

1) oxidized impurity (not more than 0.5%);

2) impurity S (not more than 0.5%); and

3) 17-desoxi-oxido intermediate or desoxi-oxido (not more than 0.5%).

The chemical structures of these three (3) main impurities weredetermined and are depicted as follows:

17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one(Oxidized Impurity)

1-Hydroxy-4,16α-dimethyl-9β,11β-oxido-17hydroxymethylcarbonylestra-1,3,5(10)triene (Impurity S)

21-Hydroxy-16α-methyl-9β,11β-oxido-pregna-1,4-diene-3.20-dione(17-desoxi-oxido Intermediate or Desoxi-Oxido Impurity) Example 2Control Formulation No. 1 Containing Desoximetasone and IsopropylMyristate (Comparative Example)

Formulation: Control formulation no. 1 containing desoximetasone andisopropyl myristate was prepared with specified ingredients as tabulatedin Table 1.

TABLE 1 Ingredients wt % Active Desoximetasone 0.25% PenetrationEnhancer Isopropyl Myristate 40.0% Solvent Purified Water 3.40% EthylAlcohol 54.75%  Surfactant Sodium Lauryl Sulfate 0.10% Polysorbate 801.50%

Preparation: The formulation was prepared as follows: desoximetasone(0.25 wt %) was first dissolved in ethyl alcohol (54.75 wt %) at roomtemperature (i.e., 25° C.). Isopropyl myristate (40.0 wt %) was thenadded to the mixture followed by addition of purified water (3.40 wt %),sodium lauryl sulfate (0.10 wt %), and polysorbate 80 (1.50 wt %). Theresulting mixture was further stirred for 15 minutes at roomtemperature.

Stability Study: We conducted the stability of desoximetasoneformulation no. 1. Formulation no. 1 containing desoximetasone andisopropyl myristate was placed in a 20-ml glass vial. Formulation no. 1was then subjected under accelerated storage condition (i.e., 40° C.,75% humidity for 12 weeks). Contents of desoximetasone and the three (3)impurities described above (i.e., oxidized impurity, impurity S, and17-desoxi-oxido intermediate) were evaluated using HPLC technique.

When formulation no. 1 was stored at 40° C., 75% humidity for 12 weeks,we surprisingly found that only one (1) of the three (3) impurities(i.e., oxidized impurity) was found to increase more than 10 fold. Thelevel of impurity S and 17-desoxi-oxido intermediate, however, was foundto be undetectable (i.e., below the limit of detection), both in thecontrol and upon accelerated storage conditions.

The level of the oxidized impurity (i.e.,17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one)exceeded the qualification threshold and identification thresholdcalculated based on the maximum daily dosage. The data is tabulated inTable 2.

TABLE 2 Content 0 Week 12 Weeks Desoximetasone 100.0% 96.24% (% TimeZero) Oxidized Impurity  0.13% 2.49% (% Area)

Characterization of the Oxidized Impurity

We have isolated the oxidized impurity (having a relative retention timeof 1.26) from the HPLC. We conducted Elemental Analysis of the isolatedoxidized impurity:

Calculated: C=67.92; H=7.54; F=5.12% Found: C=68.20; H=7.41, F=5.47%

Conformed with the formula of a hemihydrate.

We analyzed the oxidized impurity using Infrared Spectroscopy. Infraredspectrum characteristic bands and assignments (KBr pellet):

3282 cm⁻1 (broad, OH),

1730 cm⁻1 (C═O),

1694 cm⁻1 (C═O),

1661 cm⁻1 (C═C),

1609 cm⁻1 (C═C).

We analyzed the oxidized impurity using Ultra-Violet Spectroscopy. TheUV maximum in methanol (1×10-4 M/L) was determined to be at wavelength239 nm, the molar absorbtivity ε was 15,500.

We analyzed the oxidized impurity using NMR Spectroscopy (D2O+NaOD) todetermine the structure. The ¹H-NMR spectrum is (δ, ppm): 7.32 (d,J=9.6, 1H, H-1), 6.19 (d, J=9.8, 1H, H-2), 5.95 (s, 1H, H-4), 4.02-4.07(m, 1H, H-11), 2.69 (complex system of lines, 1H), 2.17-2.21 (complexsystem of lines, 3H), 1.30-1.81 complex system of lines, 7H), 1.39 (s,3H, CH₃-19), 1.25-1.47 (m, 1H), 0.75 (d, 3H, CH₃-22), 0.74 (s, 3H,CH₃-18).

High Resolution Mass Spectrometry was conducted. The molecular ion atm/z 363.1891 (MH+) was found to correspond to formula C₂₁H₂₇FO₄. Thisstructural analysis confirmed the identity of the oxidized impurity as17-carboxy-9α-fluoro,11β-hydroxy-16α-methylandrosta-1,4-diene-3-one. Themelting point of the oxidized impurity was determined to be >250° C.

Profile of Other Impurities: In addition to the three (3) impurities (asdescribed above), we also monitored other impurities that may be presentin the formulation during the accelerated storage conditions. Table 3depicts the complete impurity profile of the control formulation no. 1after storage at 40° C. and 75% humidity for 12 weeks. The main impuritywas the oxidized impurity, which has an elution retention time (RT) of22.596. The % area of the oxidized impurity was 2.49% area. There weresix (6) minor impurities with different retention times. The totalamount of these minor impurities was less than about 0.6% area. Based ontheir retention times, it is believed that they do not overlap withthose of: 1) impurity S, and 2) 17-desoxi-oxido intermediate. Thechemical identity of these six (6) minor impurities is presentlyunknown.

TABLE 3 RT Impurity % Area 9.791 Unknown 0.09 13.030 Unknown 0.06 13.583Unknown 0.04 22.596 Oxidized Impurity 2.49 37.687 Unknown 0.11 44.502Unknown 0.08 45.737 Unknown 0.22

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 1 at time zero is shown in FIG. 1.

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 1 after storage at 40° C./75% relative humidity for 12weeks is shown in FIG. 2.

Example 2 Formulation Nos. 2-6 Containing Desoximetasone, IsopropylMyristate and Various Anti-Oxidants

Formulation: We evaluated if anti-oxidants may reduce the formation ofimpurities during the accelerated storage condition. Variousanti-oxidants were added to the formulation nos. 2-6 containingdesoximetasone and isopropyl myristate and impurity profiles weredetermined. Specifically, anti-oxidants butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), ascorbic acid, tartaric acid andDL-alpha tocopherol in combination with citric acid were used at variousconcentrations as tabulated in Table 4.

TABLE 4 Formul. Formul. Formul. Formul. Formul. Ingredients No. 2 No. 3No. 4 No. 5 No. 6 Active Desoxi-  1.0%  1.0%  1.0%  1.0%  1.0% metasonePenetration Enhancer Isopropyl 40.0% 40.0% 40.0% 40.0% 40.0% MyristateSolvent Purified 1.10% 0.90% 1.35% 1.3% 1.40% Water Ethyl 57.10% 57.10%  57.10%  57.10%  57.10%  Alcohol Surfactant SLS 0.10% 0.10% 0.10%0.10% 0.10% Polysorbate 0.15% 0.15% 0.15% 0.15% 0.15% 80 AntioxidantsCitric Acid 0.25% 0.25% 0.25% 0.25% 0.25% BHA 0.10% — — — — BHT 0.20%0.50% — — — Ascorbic — — 0.05% — — Acid Tartaric Acid — — — 0.10% —DL-alpha — — — — 0.002%  Tocopherol

Preparation: The formulation was prepared as follows: desoximetasone(1.0 wt %) was dissolved in ethyl alcohol (57.10 wt %) at roomtemperature (i.e., 25° C.). Isopropyl myristate (40.0 wt %) was added tothe mixture followed by purified water, sodium lauryl sulfate (0.10 wt%), and polysorbate 80 (0.15 wt %). Antioxidants were added and mixed inaccordance to the specific formulation. The resulting mixtures werefurther stirred for 15 minutes at room temperature.

Stability Study: We conducted the stability of formulation nos. 2-6 bysubjecting the formulations under accelerated storage condition (i.e.,50° C. at for 4 weeks). Formulation no. 2-6 containing desoximetasoneand isopropyl myristate was placed in a 20-ml glass vial stored at 50°C. for 4 weeks. Content of desoximetasone and impurities were evaluatedusing HPLC technique. The data is tabulated in Table 5.

TABLE 5 Time Formul. Formul. Formul. Formul. Formul. Content points No.2 No. 3 No. 4 No. 5 No. 6 Desoxi- 0 week 100.0% 100.0% 100.0% 100.0%100.0% metasone 2 weeks 95.60% 96.10% 96.80% 96.70% 98.90% (% Time Zero)4 weeks 90.40% 88.30% 95.50% 92.30% 93.90% Oxidized 0 week  0.13%  0.14% 0.13%  0.13%  0.11% Impurity 2 weeks  1.13%  0.96%  0.92%  1.45%  1.0%(% Area) 4 weeks  3.15%  3.37%  2.52%  4.17%  2.90%

Impurity Profile: Table 6 depicts the impurity profile of theformulation nos. 2-6 after accelerated storage condition (i.e., 50° C.for 4 weeks). The main impurity present in the formulation nos. 2-6 wasthe oxidized impurity(17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one).Anti-oxidants simply did not inhibit the formation of the oxidizedimpurity in all the formulations tested (See, Table 5).

Not only anti-oxidants fail to inhibit the formation of oxidizedimpurity, it led to the generation of a lot more impurities.Specifically, a total of twelve (12) minor impurities were eluted fromformulation no. 2, five (5) minor impurities were eluted fromformulation no. 3, nine (9) minor impurities were eluted fromformulation no 4 and six (6) minor impurities were eluted formformulation nos. 5 and 6.

It is found that these minor impurities do not share the retention timewith that of i) the oxidized impurity, ii) impurity S and iii)17-desoxi-oxido intermediate. Accordingly, it is concluded that thechemical structure of these minor impurities are not the same as that ofi) the oxidized impurity, ii) impurity S and iii) 17-desoxi-oxidointermediate. However, the exact chemical structure of these minorimpurities has not been determined and is presently unknown.

Of note is the observation that the oxidized impurity has a distinctretention time (i.e., about 21.994 to about 22.996) for formulation nos.2-6, due to the intrinsic variations of the HPLC conditions. The maximum% area of the oxidized impurity was 4.17 (i.e., formulation no. 5). Theminimum % area of the oxidized impurity was 2.52 (i.e., formulation no.4). (See, Table 6).

The total % area of the minor impurities was less than about 4% area.The maximum % area of the minor impurities was 3.42 (i.e., formulationno. 2). The minimum % area of the minor impurities was 1.13 (i.e.,formulation no. 5). (See, table 6).

TABLE 6 Impurity Formul. Formul. Formul. Formul. Formul. Type No. 2 No.3 No. 4 No. 5 No. 6 Oxidized 3.15% 3.37% 2.52% 4.17% 2.90% Impurity (RT(RT (RT (RT (RT 22.976) 22.639) 22.453) 22.392) 21.994) Unknown 0.05% —0.26% — — Impurity (RT 6.264) (RT 6.672) — — 0.04% — — (RT 8.946) 0.03%— 0.07% 0.07% 0.06% (RT 9.946) (RT 9.765) (RT (RT 9.730) 9.581) 0.09% —— — — (RT 10.999) 0.10% 0.06% — 0.04% 0.04% (RT (RT (RT (RT 12.414)12.281) 12.979) 12.651) 0.29% 0.18% 0.04% 0.09% 0.11% (RT (RT (RT (RT(RT 13.826) 13.694) 13.116) 13.514) 13.273) 0.09% — 0.06% — — (RT (RT15.169) 13.519) 0.19% — — — (RT 16.063 0.09% — — — — (RT 21.475) 0.03% —— — — (RT 33.446) 0.26% 0.28% 0.35% — — (RT (RT (RT 34.556) 34.079)33.775) 0.57% 0.45% 0.15% 0.29% 0.33% (RT (RT (RT (RT (RT 38.438)37.860) 37.542) 37.333) 36.645) — — 0.04% 0.05% 0.05% (RT (RT (RT44.286) 44.110) 43.147) 1.63% 1.14% 0.29% 0.59% 0.68% (RT (RT (RT (RT(RT 46.576) 45.821) 45.503) 45.245) 44.430)

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 5 (containing anti-oxidant of citric acid and tartaricacid) at time zero is shown in FIG. 3.

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 5 (containing anti-oxidant of citric acid and tartaricacid) after storage at 50° C. for 4 weeks is shown in FIG. 4.

Example 5 Formulations Nos. 7-10 Containing Desoximetasone and IsopropylAlcohol and A Mixture of Mineral Oil Light and Oleyl Alcohol

Formulation: Formulations nos. 7-10 containing desoximetasone andisopropyl myristate were prepared with specified ingredients as listedin Table 7.

TABLE 7 Formu- Formu- lation lation Formulation Formulation IngredientsNo. 7 No. 8 No. 9 No. 10 Active Desoximetasone 0.25% 0.25% 0.25% 0.25%Penetration Enhancer Isopropyl Myristate 10.0% 40.0% 10.0% 10.0% SolventIsopropyl Alcohol 25.0% 20.0% 30.0% 40.0% Stabilizing agent OleylAlcohol  8.0%  5.0%  8.0%  5.0% Mineral Oil Light 43.60%  29.60% 43.60%  37.20%  Other Excipients Menthol 0.05% 0.05% 0.05% 0.05%Cyclomethicone  8.0%  5.0%  8.0% 7.50% Povidone-K90 0.10% 0.10% 0.10% —Isopropyl Palmitate  5.0% — — —

Preparation: The formulation nos. 7-10 were prepared as follows:desoximetasone (0.25 wt %) was first dissolved in isopropyl alcohol atroom temperature (i.e., 25° C.). Isopropyl myristate was added to themixture followed by oleyl alcohol, cyclomethicone and mineral oil light,menthol and isopropyl palmitate. Where applicable, povidone-K90 (i.e.,formulations 8-10) was premixed in isopropyl alcohol. The resultingmixture was further stirred for 15 minutes at room temperature.

Stability Study: We conducted the stability studies of formulation nos.7-10 by subjection the formulations under the accelerated storagecondition (i.e., 40° C. at 75% relative humidity for 12 weeks).Formulation nos. 7-10 containing desoximetasone and isopropyl myristatewere placed in a 20-ml glass vials. Content of desoximetasone andimpurities were evaluated using HPLC technique. The data is tabulated inTable 8.

TABLE 8 Formul. Formul. Formul. Formul. Content Time points No. 7 No. 8No. 9 No. 10 Desoximetasone  0 week 100.0% 100.0%  100.0%  100.0%  (%Time Zero)  4 weeks 100.0% 100.0%  100.5%  100.5%   8 weeks 98.48%100.49%  101.03%  100.5%  12 weeks 100.0% 100.62%  102.17%  100.62% Oxidized Impurity  0 week  0.05% 0.05% 0.10% 0.07% (% Area)  4 weeks 0.07% 0.07% 0.10% 0.09%  8 weeks  0.24%  0.10% 0.11% 0.20% 12 weeks 0.49%  0.39% 0.17% 0.26%

Impurity Profile: Table 9 depicts the impurity profile of theformulation nos. 7-10 after accelerated storage condition (i.e., at 40°C. at 75% humidity for 12 weeks). The main impurity present in theformulation nos. 7-10 was the oxidized impurity(17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one).The oxidized impurity has a distinct retention time of about 23.612 toabout 30.951, due to the intrinsic variations of the HPLC runningconditions. The maximum % area of the oxidized impurity was 0.53 (i.e.,formulation no. 7). The minimum % area of the oxidized impurity was 0.17(i.e., formulation no. 9).

At least one minor impurity was observed in each of the formulation nos.7-10. This minor impurity for formulation no. 7 has a retention time ofabout 6.378; while the minor impurity of the formulation nos. 8-10 has aretention time of about 28.063 to about 28.512, due to the intrinsicvariations of the HPLC running conditions. Based on the difference inthe retention time, the minor impurity present in formulation no. 7appears to be different from that of formulations 8-10. The identity ofthe minor impurity is presently unknown. The maximum % area of the minorimpurity was 0.13 (i.e., formulation no. 7). The minimum % area of theminor impurity was 0.09 (i.e., formulation nos. 8-10). Based on theirretention times, it is believed that they do not overlap with thoseof: 1) impurity S, and 2) 17-desoxiosido.

TABLE 9 Impurity Formulation Formulation Formulation Formulation TypeNo. 7 No. 8 No. 9 No. 10 Oxidized 0.53% 0.39% 0.17% 0.26% Impurity (RT23.612) (RT 30.472) (RT 30.718) (RT 30.951) Unknown 0.13% 0.09% 0.09%0.09% Impurity (RT 6.378) (RT 28.063) (RT 28.293) (RT 28.512)

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 7 (containing a stabilizing agent of a mixture ofmineral oil and oleyl alcohol) at time zero is shown in FIG. 5.

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 7 (containing a stabilizing agent of a mixture ofmineral oil and oleyl alcohol) after storage at 40° C./75% relativehumidity for 12 weeks is shown in FIG. 6.

Example 6 Formulation No 11 Containing Desoximetasone and IsopropylMyristate in a Mixture of Mineral Oil and Glyceryl Oleate

Formulation: Control formulation no. 11 containing desoximetasone andisopropyl myristate was prepared with specified ingredients as tabulatedin Table 10.

TABLE 10 Ingredients wt % Active Desoximetasone 0.30% PenetrationEnhancer Isopropyl Myristate 31.35%  Solvent Isopropyl Alcohol 23.40% Stabilizing agent Glyceryl Oleate 0.90% Mineral Oil 44.0% OtherExcipients Menthol 0.05%

Preparation: The formulation no. 11 was prepared as follows:desoximetasone (0.30 wt %) was dissolved in isopropyl alcohol (23.40 wt%) at room temperature (i.e., 25° C.). Isopropyl myristate (31.35 wt %)was added to the mixture followed by glyceryl oleate (0.90 wt %),mineral oil (44.0 wt %) and menthol (0.05 wt %). The resulting mixturewas further stirred for 15 minutes at room temperature.

Stability Study: We conducted the stability study for formulation no. 11by subjecting the formulation under accelerated storage condition (i.e.,40° C. at 75% humidity for 12 weeks). Formulation no. 11 was placed in a20-ml glass vial and stored at 40° C. at 75% humidity for 12 weeks.Content of desoximetasone and impurities were evaluated using HPLCtechnique. The data is tabulated in Table 11.

TABLE 11 Content 0 Week 12 Weeks Desoximetasone 100.0% 99.16% (% TimeZero) Oxidized Impurity  0.05% 0.07% (% Area)

Impurity Profile: Table 12 depicts the impurity profile of theformulation no. 11 after the accelerated storage condition (i.e., 40° C.and 75% humidity for 12 weeks). The main impurity present in formulationno. 11 was the oxidized impurity(17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one).The oxidized impurity has a retention time of about 23.7. The % area ofthe oxidized impurity was 0.07. There was only one minor impuritypresent in the formulation no. 11. The total % area of the minorimpurity was about 0.11.

TABLE 12 Formulation No. Impurity Type RT 11 Oxidized Impurity 23.70.07% Unknown 6.405 0.11%

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 11 (containing a stabilizing agent of a mixture ofmineral oil and glyceryl oleate) at time zero is shown in FIG. 7.

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 11 (containing a stabilizing agent of a mixture ofmineral oil and glyceryl oleate) after storage at 40° C./75% relativehumidity for 12 weeks is shown in FIG. 8.

Example 9 Formulation No. 12 Containing Desoximetasone and IsopropylMyristate in Propellant

Formulation: Formulation no. 12 containing desoximetasone and isopropylmyristate was prepared with specified ingredients as tabulated in Table13.

TABLE 13 Ingredients wt % Active Desoximetasone 0.07% PenetrationEnhancer Isopropyl Myristate 10.0% Solvent Purified Water 0.85% EthylAlcohol 13.70%  Surfactant Sodium Lauryl Sulfate 0.03% Polysorbate 800.35% Propellant 1,1,1,2-Tetrafluoroethane   75% (Dymel 134a/P ®)

Preparation: The formulation was prepared as follows: desoximetasone(0.07 wt %) was first dissolved in ethyl alcohol (13.70 wt %) at roomtemperature (i.e., 25° C.). Isopropyl myristate (10.0 wt %) was added tothe mixture followed by purified water (0.85 wt %), sodium laurylsulfate (0.03 wt %), and polysorbate 80 (0.35 wt %). The resultingmixture was further stirred for 15 minutes at room temperature. Theresulting mixture was first introduced into a coated aluminum canequipped with a continuous spray valve. 75 wt % propellant (i.e.,1,1,1,2-Tetrafluoroethane, Dymel 134a/P®) was then introduced into thealuminum can quantity sufficient to make up the total volume to 100 wt%.

Stability Study: We conducted the stability of formulation no. 12 bysubjecting the formulation under accelerated storage condition (i.e.,40° C. at 75% humidity for 12 weeks. Formulation no. 12 containingdesoximetasone and isopropyl myristate was packaged in 100-ml coatedaluminum canisters and stored at 40° C. at 75% humidity for 12 weeks.Content of desoximetasone and impurities were evaluated using HPLCtechnique. The data is tabulated in Table 14.

TABLE 14 Content 0 Week 12 Weeks Desoximetasone 100.0% 92.0% (% TimeZero) Oxidized Impurity  0.53% 0.45% (% Area)

Impurity Profile: Table 15 depicts the impurity profile of theformulation no. 12 after storage at 40° C. and 75% humidity for 12weeks. The main impurity present in formulation no. 12 was the oxidizedimpurity(17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one).The oxidized impurity has a retention time (RT) of about 22.110. The %area of the oxidized impurity was 0.45. No minor impurity was found tobe present in formulation no. 12, either at time zero

Example 9 Formulation No. 12 Containing Desoximetasone and IsopropylMyristate in Propellant

Formulation: Formulation no. 12 containing desoximetasone and isopropylmyristate was prepared with specified ingredients as tabulated in Table13.

TABLE 13 Ingredients wt % Active Desoximetasone 0.07% PenetrationEnhancer Isopropyl Myristate 10.0% Solvent Purified Water 0.85% EthylAlcohol 13.70%  Surfactant Sodium Lauryl Sulfate 0.03% Polysorbate 800.35% Propellant 1,1,1,2-Tetrafluoroethane   75% (Dymel 134a/P ®)

Preparation: The formulation was prepared as follows: desoximetasone(0.07 wt %) was first dissolved in ethyl alcohol (13.70 wt %) at roomtemperature (i.e., 25° C.). Isopropyl myristate (10.0 wt %) was added tothe mixture followed by purified water (0.85 wt %), sodium laurylsulfate (0.03 wt %), and polysorbate 80 (0.35 wt %). The resultingmixture was further stirred for 15 minutes at room temperature. Theresulting mixture was first introduced into a coated aluminum canequipped with a continuous spray valve. 75 wt % propellant (i.e.,1,1,1,2-Tetrafluoroethane, Dymel 134a/P®) was then introduced into thealuminum can quantity sufficient to make up the total volume to 100 wt%.

Stability Study: We conducted the stability of formulation no. 12 bysubjecting the formulation under accelerated storage condition (i.e.,40° C. at 75% humidity for 12 weeks). Formulation no. 12 containingdesoximetasone and isopropyl myristate was packaged in 100-ml coatedaluminum canisters and stored at 40° C. at 75% humidity for 12 weeks.Content of desoximetasone and impurities were evaluated using HPLCtechnique. The data is tabulated in Table 14.

TABLE 14 Content 0 Week 12 Weeks Desoximetasone 100.0% 92.0% (% TimeZero) Oxidized Impurity  0.53% 0.45% (% Area)

Impurity Profile: Table 15 depicts the impurity profile of theformulation no. 12 after storage at 40° C. and 75% humidity for 12weeks. The main impurity present in formulation no. 12 was the oxidizedimpurity(17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-one).The oxidized impurity has a retention time (RT) of about 22.110. The %area of the oxidized impurity was 0.45. No minor impurity was found tobe present in formulation no. 12, either at time zero or after storageat 40° C. and 75% humidity for 12 weeks. These data support that thestabilizing agent is extremely effective in inhibiting the production ofboth oxidized impurity as well as minor impurities.

TABLE 15 Impurity Name RT Formulation No. 12 Oxidized 22.110 0.45%Unknown Impurity — —

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 12 (containing a stabilizing agent of a propellant) attime zero is shown in FIG. 9.

The entire HPLC chromatogram summarizing the impurity profile forformulation no. 11 (containing a stabilizing agent of a propellant)after storage at 40° C./75% relative humidity for 12 weeks is shown inFIG. 10.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. The disclosures of thecited publications are incorporated herein in their entireties byreference. It is to be understood, however, that the scope of thepresent invention is not to be limited to the specific embodimentsdescribed above. The invention may be practiced other than asparticularly described and still be within the scope of the accompanyingclaims.

1. A liquid formulation comprising: a) about 0.01 wt % to about 2.5 wt %desoximetasone; b) about 10 wt % to about 70 wt % isopropyl myristate;c) about 20 wt % to about 70 Wt % C₂-C₄ alcohol; and d) a stabilizingagent selected from the group consisting of an oleaginous vehicle and apropellant, wherein the stabilizing agent is present in a sufficientamount to reduce the formation of less than about 1 wt %17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-oneafter storage at 40° C., 75% relative humidity for 3 months.
 2. Theliquid formulation of claim 1, wherein the desoximetasone is about 0.1wt % to about 1 wt %.
 3. The liquid formulation of claim 1, wherein thedesoximetasone is about 0.25 wt %.
 4. The liquid formulation of claim 1,wherein the isopropyl myristate is about 25 wt % to about 55 wt %. 5.The liquid formulation of claim 1, wherein the isopropyl myristate isabout 40 wt %.
 6. The liquid formulation of claim 1, wherein the C₂-C₄alcohol is ethyl alcohol.
 7. The liquid formulation of claim 1, whereinthe C₂-C₄ alcohol is isopropanol.
 8. The liquid formulation of claim 1,wherein the C₂-C₄ alcohol is about 30 wt % to about 60 wt %.
 9. Theliquid formulation of claim 1, wherein the C₂-C₄ alcohol is about 40 wt%.
 10. The liquid formulation of claim 1, wherein the oleaginous vehicleis selected from the group consisting of mineral oil, and light mineraloil.
 11. The liquid formulation of claim 1, wherein the oleaginousvehicle is mineral oil.
 12. The liquid formulation of claim 1, whereinthe oleaginous vehicle is present in the amount of about 10 wt % toabout 60 wt %.
 13. The liquid formulation of claim 1, wherein theoleaginous vehicle is present in the amount of about 20 wt % to about 50wt %.
 14. The liquid formulation of claim 1, wherein the oleaginousvehicle is present in the amount of about 40 wt %.
 15. The liquidformulation of claim 1, wherein the oleaginous vehicle further comprisesa ester of a glycerin and a C₁₅-C₂₅ fatty acid.
 16. The liquidformulation of claim 1, wherein the ester is a monoester.
 17. The liquidformulation of claim 15, wherein the C₁₅-C₂₅ fatty acid is oleic acid.18. The liquid formulation of claim 15, wherein the ester is glyceryloleate.
 19. The liquid formulation of claim 15, wherein the ester ispresent in the amount of about 0.5 wt % to about 10 wt %.
 20. The liquidformulation of claim 15, wherein the ester is present in the amount ofabout 1 wt % to about 8 wt %.
 21. The liquid formulation of claim 15,wherein the ester is present in the amount of about 5 wt %.
 22. Theliquid formulation of claim 1, wherein the oleaginous vehicle furthercomprises a C₁₅-C₂₅ fatty alcohol.
 23. The liquid formulation of claim22, wherein the C₁₅-C₂₅ fatty alcohol is selected from the groupconsisting of lauryl alcohol, myristyl alcohol, palmityl alcohol,stearyl alcohol, linoleyl alcohol, and oleyl alcohol.
 24. The liquidformulation of claim 22, wherein the C₁₅-C₂₅ fatty alcohol is oleylalcohol.
 25. The liquid formulation of claim 22, wherein the C₁₅-C₂₅fatty alcohol is present in the amount of about 0.5 wt % to about 10 wt%.
 26. The liquid formulation of claim 22, wherein the C₁₅-C₂₅ fattyalcohol is present in the amount of about 1 wt % to about 8 wt %. 27.The liquid formulation of claim 22, wherein the C₁₅-C₂₅ fatty alcohol ispresent in the amount of about 5 wt %.
 28. The liquid formulation ofclaim 1, wherein the propellant is selected from the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, butane,isobutane, propane, and dimethyl ether.
 29. The liquid formulation ofclaim 1, wherein the propellant is 1,1,1,2-tetrafluoroethane.
 30. Theliquid formulation of claim 1, wherein the propellant is about 20 wt %to about 95 wt %.
 31. The liquid formulation of claim 1, wherein thepropellant is about 40 wt % to about 80 wt %.
 32. The liquid formulationof claim 1, wherein the propellant is about 20 wt % to about 75 wt %.33. The liquid formulation of claim 1, further comprising a surfactant.34. The liquid formulation of claim 33, wherein the surfactant selectedfrom the group consisting of sodium lauryl sulfate, and polysorbate 80.35. The liquid formulation of claim 33, wherein the surfactant ispresent in the amount of about 0.5 wt % to about 5 wt %.
 36. The liquidformulation of claim 1, further comprising water.
 37. The liquidformulation of claim 36, wherein the water is present in the amount ofabout 1 wt % to about 10 wt %.
 38. The liquid formulation of claim 1,wherein the liquid formulation is after storage at 50° C. for 4 weeks.39. The liquid formulation of claim 1, wherein the liquid formulation isdelivered via a pump delivery system.
 40. The liquid formulation ofclaim 1, wherein the liquid formulation is delivered via an aerosolizeddelivery system.
 41. The liquid formulation of claim 40, wherein theaerosolized delivery system contains a can equipped with a continuousvalve.
 42. The liquid formulation of claim 40, wherein the aerosolizeddelivery system contains a can equipped with a metered-dosed valve. 43.The liquid formulation of claim 1, wherein the liquid formulation is afoam.
 44. The liquid formulation of claim 42, wherein the foam is aquick-break form.
 45. A method of treating a corticosteroid responsivedermatosis in a mammal comprising the step of topical administering theaerosolized formulation of claim
 1. 46. The method of claim 45, whereinthe corticosteroid responsive dermatosis is selected from the groupconsisting of plaque psoriasis, and atopic dermatitis.
 47. A process forpreparing a liquid formulation comprising: a) mixing desoximetasone in aC₂-C₄ alcohol to from a mixture; b) adding isopropyl myristate in themixture; and c) adding stabilizing agent selected from the groupconsisting of an oleaginous vehicle and a propellant to the mixture,wherein the added stabilizing agent is in an amount sufficient to reducethe formation of less than about 1 wt %17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-oneafter storage at 40° C., 75% relative humidity for 3 months.
 48. Aprocess for preparing an aerosolized formulation of desoximetasonecomprising the step of filling an aerosol formulation into a containerequipped with a continuous valve, said aerosol formulation contains: a)about 0.01 wt % to about 2.5 wt % desoximetasone; b) about 10 wt % toabout 70 wt % isopropyl myristate; c) about 20 wt % to about 70 wt %C₂-C₄ alcohol; and d) a stabilizing agent selected from the groupconsisting of an oleagenous vehicle and a propellant, wherein thestabilizing agent is in an amount sufficient to reduce the formation ofless than about 1 wt %17-carboxy-9α-fluoro-11β-hydroxy-16α-methyl-androsta-1,4-diene-3-oneafter storage at 40° C., 75% relative humidity for 3 months.